scholarly journals Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

ESMO Open ◽  
2020 ◽  
Vol 5 (5) ◽  
pp. e000926
Author(s):  
Gerardo Colon-Otero ◽  
Valentina Zanfagnin ◽  
Xiaonan Hou ◽  
Nathan R Foster ◽  
Erik J Asmus ◽  
...  
Keyword(s):  
Phase Ii ◽  
Oestrogen Receptor ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Low Grade ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Er Positive ◽  
Registration Number ◽  
Pdx Models

ObjectiveWe describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive.MethodsPatients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies.ResultsForty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models.ConclusionRibociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models.Trial registration numberClinicalTrials.gov registry (NCT02657928).

Phase II consolidation trial with anti-Lewis-Y monoclonal antibody (hu3S193) in platinum-sensitive ovarian cancer after a second remission

2021 ◽  
pp. ijgc-2020-002239
Author(s):  
Oren Smaletz ◽  
Gustavo Ismael ◽  
Maria Del Pilar Estevez-Diz ◽  
Ivana L O Nascimento ◽  
Ana Luiza Gomes de Morais ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Monoclonal Antibody ◽  
Epithelial Ovarian Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Lewis Y

ObjectiveTo investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy.MethodsThis single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics.ResultsTwenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6–13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%).ConclusionsHu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy.Trial registrationNCT01137071.

NGR-hTNF and doxorubicin in relapsed small-cell lung cancer (SCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7085-7085 ◽  
Author(s):  
Raffaele Cavina ◽  
Vanesa Gregorc ◽  
Silvia Novello ◽  
Francesco Grossi ◽  
Armando Santoro ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Duration ◽  
Human Tumor ◽  
Progression Free Survival ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Grade 3 ◽  
Further Development ◽  
Necrosis Factor

7085 Background: By selectively damaging tumor vasculature, NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is able to improve intratumoral uptake of doxorubicin (D). A phase I trial selected NGR-hTNF 0.8 µg/m2/day(d)1 and D 75 mg/m2/d1 every 3 weeks (q3w) for phase II. Methods: SCLC pts failing one or more platinum-based regimen received NGR-hTNF until progressive disease (PD) and D up to 550 mg/m2. This phase II trial (n=27 pts) had progression-free survival (PFS) as primary end point, with tumor response assessed q6w by RECIST, while secondary end points included adverse events (AEs), disease control rate (DCR), and overall survival (OS). Results: Among 28 pts enrolled (median age 63 years; M/F 19/9; PS 0/1-2 13/15; prior lines 1/2-3 20/8), 16 pts had platinum-resistant (R) disease (PD≤3 months) and 12 pts platinum-sensitive (S) disease (PD>3 months). At baseline, median neutrophil to lymphocyte ratio (NLR) was 4 (range 1-20). A total of 114 cycles were given (range 1-10), with 13 pts (46%) having ≥ 4 cycles and 9 pts (32%) ≥ 6 cycles. No grade 3/4 AEs related to NGR-hTNF were noted, while grade 1/2 AEs were transient chills (61%). NGR-hTNF did not apparently increase D-related AEs. Median PFS was 3.2 months (95% CI 2.6-3.8) and 1-year OS rate was 34%. Overall, DCR was 55% (95% CI 35-74), comprising 6 partial responses (22%; median duration: 6.3 months) and 9 stable diseases (33%; median duration: 4.1 months). Mean changes from baseline in target tumor size after 2, 4, and 6 cycles were -9%, -29%, and -32%, respectively for R disease and -11%, -20%, and -43%, respectively for S disease. In pts pretreated with ≥ 2 lines, DCR was 75%, median PFS was 5.1 months, and 1-year OS rate was 44%. In pts with R or S disease, DCR were 50% and 58% (p=.72), median PFS were 2.7 and 4.1 months (p=.07), and 1-year OS rates were 27% and 42% (p=.65), respectively. At multivariate analyses, PFS was not related to baseline characteristics, while an improved OS was associated only with a low NLR. The 1-year OS rate was 48% in pts with NLR ≤ 4 and 10% in pts with NLR > 4 (p=.007), while in pts with NLR ≤ 4, 1-year OS rate was 46% in R disease and 50% in S disease. Conclusions: This combination is well tolerated and active in platinum resistant and sensitive SCLC and further development is of interest.

Phase II Study of Pomalidomide (Pom) in Genomically Defined High Risk Relapsed and Refractory Multiple Myeloma (RRMM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4083-4083 ◽  
Author(s):  
Saad Z Usmani ◽  
Emily Hansen ◽  
Doug Steward ◽  
Sarah Waheed ◽  
Susan B. Panozzo ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Gene Model ◽  
Free Survival ◽  
Increased Risk

Abstract Abstract 4083 Background: Pom is a third generation immunomodulatory drug (IMiD) which has demonstrated safety and efficacy in RRMM with prior exposure/resistant to other IMiDs and bortezomib. This is the first report on a phase II clinical trial employing Pomalidomide (Pom) in genomically defined high risk RRMM. Methods: First cycle Pom was given at 4mg orally Days 1–21 every 28 days; dexamethasone (DEX) or bortezomib (BOZ) could be given in absence of PR or better from Cycle #3. In the absence of at least PR, Pom dose was escalated to 5mg. Cox regression modeling was employed for univariate and multivariate analyses, whereas Kaplan-Meier curves were used for overall survival (OS) and progression free survival (PFS). Results: 30 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 47%, ISS stage >=II was seen in 74% of patients, cytogenetic abnormalities (CA) within 6 months in 79%, and GEP-defined high risk in 66% by GEP70-gene model, 97% by GEP80-gene model, 13% had extramedullary disease (EMD), and 7% had secondary plasma cell leukemia (SPCL). 26/30 patients (87%) had prior autologous stem cell transplant, 23/30 patients (77%) had had at least 2 transplants. 22 patients (73%) had disease progression while on lenalidomide, bortezomib or both within 60 days of enrollment. At least 2 cycle of treatment were administered to 28 (93%) patients enrolled, 20 (67%) patients received >4 cycle of treatment and 16 (53%) received > 6 cycles. 15 patients (50%) discontinued therapy primarily due to progression or death. 5 (17%) patients achieved PR or better as best response. PFS benefit was observed in older patients (HR=0.29, p=0.008), with high LDH presenting an increased risk for OS (HR=14.64, p=0.013.) Most common toxicities, counting all toxicities (>=grade 3) were: thrombocytopenia (63%), leukopenia (63%), anemia (40%), hypophosphatemia (20%) and hypocalcemia (23%). Overall and progression- free survival at 12 months were 64% and 20%, respectively. Conclusions: The present trial is the first investigation evaluating Pom's clinical activity in high risk RRMM and demonstrates good anti-myeloma activity in this heavily pre-treated patient population. Given the activity in poor prognostic clinical features such as EMD and SPCL, there is precedence to evaluate Pom as an IMiD of choice in combination with other novel agents for this subset of RRMM. Disclosures: No relevant conflicts of interest to declare.

Panitumumab in platinum-sensitive epithelial ovarian cancer patients with KRAS wild-type: The PROVE-study, a phase II randomized multicenter study of the North-Eastern German Society of Gynaecologic Oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5558-5558 ◽  
Author(s):  
Radoslav Chekerov ◽  
Peter Klare ◽  
Petra Krabisch ◽  
Jochem Potenberg ◽  
Georg Heinrich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Ca 125 ◽  
Wild Type ◽  
Skin Reactions ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy

5558 Background: For ovarian cancer (OC) patients with platinum-sensitive recurrence the addition of new biologic agents to chemotherapy may improve survival. Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). The purpose of this trial was to investigate the therapeutic efficacy of panitumumab in the combination with carboplatin-based chemotherapy in relation to the respective standard combination in patients with a KRAS wildtype with platinum-sensitive recurrent ovarian cancer (NCT01388621). Methods: Major eligibility criteria were pretreated platinum-sensitive epithelial ovarian/ fallopian/ peritoneal cancer and no more than 2 prior treatments for this disease. Only patients with measurable disease or elevated CA125 and with KRAS wild type were eligible. Patients were treated with Carboplatin AUC4/Gemcitabine 1000 mg/m² or Carboplatin AUC5/PLD 40 mg/m² and randomized to panitumumab 6 mg/kg day 1 and day 15, every 3 or 4 weeks. Tumor assessment was performed at baseline and at every third cycle according to CT-scan and CA-125 criteria. Results: In this multi-institutional phase II trial 102 patients were randomized and 96 enrolled for the final analysis. Progression-free survival in the intention-to-treat population (N=96) was 9.5 vs. 10.7 months (HR 0.829, 95%CI of 8.5-11.6 months vs 8.5-13.1 months) for the experimental vs. standard arm, p=0.45. Data of overall survival are not jet evaluable. The most common treatment related grade 3+ toxicities included hematologic toxicity (54%), skin reactions (18%) and gastrointestinal events (16%). Conclusions: The addition of panitumumab to platinum-based chemotherapy for recurrent ovarian cancer does not influence efficacy and progression-free survival in platinum sensitive patients, while no new additional toxicity aspects for panitumumab were evaluated. Clinical trial information: NCT01388621.

A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 410-410 ◽  
Author(s):  
Andrea Wang-Gillam ◽  
Lingling Du ◽  
Andrea S. Teague ◽  
Rama Suresh ◽  
Kian-Huat Lim ◽  
...  
Keyword(s):  
Amino Acids ◽  
Phase I ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Ductal Adenocarcinoma ◽  
Clinical Activity ◽  
Free Survival ◽  
Dose Levels ◽  
Clinical Trial Information

410 Background: Recent advances in front-line therapy have improved survival in patients with advanced PDAC. A fluorouracil-based regimen is recommended for patients who progress on a gemcitabine-based therapy. Tosedostat is an oral aminopeptidase inhibitor that disrupts the cleavage of amino acids from peptides downstream of proteasomal degradation. It prevents the recycling of free amino acids, leads to intracellular depletion of amino acids, and triggers an amino acid deprivation response that subsequently results in apoptosis. Because PDAC cells frequently upregulate expression of these aminopeptidases, tosedostat offers therapeutic promise, particularly in combination with fluoropyrimidines. Methods: This is a single institution phase I/II trial to evaluate the safety and toxicity of tosedostat plus capecitabine in patients with metastatic PDAC progressed on a gemcitabine-based therapy. The phase I portion is being conducted in a dose de-escalation fashion, with two dose levels of tosedostat (120 mg or 60 mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one out of 6 patients in the tosedostat (120 mg) cohort experience a dose limiting toxicity (DLT), then 6 more will be enrolled to the tosedostat (60 mg) cohort. The primary objective of the phase I portion is to determine the optimal phase II dose. The primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives include the overall response rate, overall survival and CA 19-9 response. To avoid futility, interim analysis is planned after 10 evaluable patients enrolled. Results: Up to date, a total of 11 patients have been enrolled in the study, and 10 patients are evaluable. No DLT have been observed. Tosedostat at a dose of 120 mg with capecitabine is extremely well tolerated. Prolonged stable disease has been observed in 4 (40%) patients with a time on treatment of 10 months, 7.5 months, 5.5 months and 4 months, and 3 of the 4 patients remain on the trial. Conclusions: The combination of tosedostat and capecitabine is a well-tolerated regimen with impressive clinical activity in the subset of patients studied thus far. Clinical trial information: NCT02352831.

Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma

2013 ◽  
Vol 31 (26) ◽  
pp. 3205-3211 ◽  
Author(s):  
Paolo A. Ascierto ◽  
David Minor ◽  
Antoni Ribas ◽  
Celeste Lebbe ◽  
Anne O'Hagan ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Mutation Status ◽  
Free Survival

Purpose Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAFV600E/K mutation–positive metastatic melanoma (mut+ MM). Patients and Methods Histologically confirmed patients with stage IV BRAFV600E/K mut+ MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAFV600E mut+ MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. Results Seventy-six patients with BRAFV600E and 16 patients with BRAFV600K mut+ MM were enrolled onto the study. In the BRAFV600E group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAFV600K mut+ MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAFV600E and BRAFV600K groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAFV600E mut+ MM patients. Conclusion Dabrafenib was well tolerated and clinically active in patients with BRAFV600E/K mut+ MM. cfDNA may be a useful prognostic and response marker in future studies.

scholarly journals The MUK eight protocol: a randomised phase II trial of cyclophosphamide and dexamethasone in combination with ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Samantha Hinsley ◽  
◽  
Katrina Walker ◽  
Debbie Sherratt ◽  
Lucy Bailey ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Phase Ii ◽  
Proteasome Inhibitor ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Trial Management ◽  
Free Survival ◽  
Refractory Multiple Myeloma

Abstract Background Multiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD. Methods MUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This ‘switch’ phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment. Discussion Development of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safety and efficacy of ICD in patients with RRMM demonstrate a toxicity profile consistent with ixazomib in combination with lenalidomide and dexamethasone, whilst the combination showed possible activity in RRMM patients. Further investigation of the anti-tumour effect of this drug in RRMM patients is therefore warranted, especially since no trials comparing CD with ICD have been completed at present. Trial registration ISRCTN number: ISRCTN58227268. Registered on 26 August 2015.

scholarly journals Selective MEK Inhibition with AZD-6244 (selumetinib) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A University of Chicago Phase II Consortium Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3990-3990
Author(s):  
Natalie Galanina ◽  
Sonali M. Smith ◽  
Chuanhong Liao ◽  
Adam M. Petrich ◽  
Bernadette Libao ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Lines ◽  
Phase Ii ◽  
Germinal Center ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Free Survival ◽  
Molecular Features

Abstract Introduction: The biology of DLBCL is complex, with a number of clinicopathologic and molecular features impacting outcome. MCT-1 is an oncogene that promotes lymphomagenesis via enhanced cell survival signaling, increased G1 cyclin/CDK activity and overriding cell cycle checkpoints; its expression is substantially elevated in DLBCL without a clear difference in germinal center versus non-germinal center subtypes. Our preliminary studies showed that 1) 85% of DLBCL samples have strong or increased expression of MCT-1via IHC, 2) MCT-1 knockdown induces apoptosis in cell lines, and 3) mutant MCT-1 protein expression attenuates the malignant phenotype via translational changes. (Dai Ca Res 2009 69(19): p. 7835-43) MCT-1 levels are directly regulated by MEK/ERK signaling, providing a rationale to test MEK pathway inhibition as a therapeutic target in DLBCL. AZD-6244 (ARRY-142886, selumetinib) is a novel second generation oral small molecule MEK inhibitor that induces dose dependent apoptosis in DLBCL cell lines and attenuates tumor growth in xenograft models. (Bhalla Blood 2011 118(4): p. 1052-61) In patients with solid tumors, AZD-6244 75mg twice daily has been established as the recommended phase II dose (RP2D). (Adjei JCO 2008 26(13): p. 2139-46) Methods: Eligible relapsed/refractory (R/R) DLBCL patients received AZD6244 hydrogen sulfate at a dose of 75 mg by mouth twice daily continuously for up to eight 28-day cycles or until disease progression or unacceptable toxicity. The primary objective of the study was overall response rate (ORR) with secondary objectives including safety, progression free survival (PFS), overall survival (OS) and pharmacodynamic (PD) analyses. The statistical design used a Simon two-stage design. Due to excessive early toxicity, the protocol was amended to reduce the dose to 50mg twice daily. Results : Sixteen R/R DLBCL pts (9 male, 7 female) with a median age of 70 years (range, 29-86 yrs), median 3 prior regimens (range, 0-6) were enrolled. Cell-of-origin was not prospectively determined, but only 3/10 pts were CD10 positive and 5/9 were MUM1 positive. The median Lactate Dehydrogenase (LDH) at study entry was 483 (range, 194-1128). Two patients withdrew consent prior to treatment exposure. Of 14 patients receiving at least one dose of selumetinib, two had stable disease and the remainder progressed. The median number of treatment cycles was one (range, 1-5). This was partly due to toxicity causing frequent dose interruptions of AZD-6244. Grade ³3 toxicities were observed in 37.5% (15.2 - 64.6%) and included anemia (44%), thrombocytopenia (25%), diarrhea (31%), transaminitis 44%), fatigue (44%); other infrequent toxicities included AV block, LV dysfunction, anorexia and rash. Median progression-free survival (PFS) in all patients was 34 days [95% CI 14-73 days]. Median overall survival (OS) was 129 days [CI 58-134 days]; all but 3 patients (including one patient lost to follow-up) have expired. Conclusion: Despite excellent preclinical rationale to test selective MEK antagonism as a means of modulating MCT-1 and MEK/ERK in DLBCL, AZD-6244 was not well tolerated and had limited clinical activity. Other MEK/ERK inhibitors with a more favorable toxicity profile and/or use of rational synergistic combination therapy should be considered to further evaluate the role of MEC inhibition in this heavily pretreated patient population. (Patel Cancer 2014 19(4): p. 799-805 (Supported by NCI contract N01-CM-2011-00071C) Disclosures Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Westin:Spectrum: Research Funding. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.

Phase II study of pembrolizumab plus SurVaxM for glioblastoma at first recurrence.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS2581-TPS2581 ◽  
Author(s):  
Manmeet Singh Ahluwalia ◽  
David M. Peereboom ◽  
Marci Ciolfi ◽  
Cathy Schilero ◽  
Brian Hobbs ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Clinical Activity ◽  
Leptomeningeal Disease ◽  
Free Survival ◽  
Apoptosis Protein ◽  
First Recurrence

TPS2581 Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with > 1 cm midline shift on imaging. Patients must not require > 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .

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